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WO2006014762A1 - Inhibiteurs d'amide beta secretase substitues - Google Patents

Inhibiteurs d'amide beta secretase substitues Download PDF

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Publication number
WO2006014762A1
WO2006014762A1 PCT/US2005/025780 US2005025780W WO2006014762A1 WO 2006014762 A1 WO2006014762 A1 WO 2006014762A1 US 2005025780 W US2005025780 W US 2005025780W WO 2006014762 A1 WO2006014762 A1 WO 2006014762A1
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Prior art keywords
compound
alkyl
substituted
aryl
mmol
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PCT/US2005/025780
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English (en)
Inventor
Ying Huang
Guoqing Li
Andrew W. Stamford
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Merck Sharp and Dohme LLC
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Schering Corp
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Priority to DE602005025363T priority Critical patent/DE602005025363D1/de
Priority to MX2007000760A priority patent/MX2007000760A/es
Priority to CA002574218A priority patent/CA2574218A1/fr
Priority to JP2007522711A priority patent/JP2008507538A/ja
Priority to AT05773473T priority patent/ATE491693T1/de
Priority to EP05773473A priority patent/EP1781625B1/fr
Publication of WO2006014762A1 publication Critical patent/WO2006014762A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to substituted amide beta secretase inhibitors, pharmaceutical compositions comprising said compounds, their use in the treatment of cardiovascular diseases, cognitive and neurodegenerative diseases, and their use as inhibitors of the Human Immunodeficiency Virus, plasmepsins, cathepsin D and protozoal enzymes.
  • AD Alzheimer's disease
  • Behavioral changes including confusion, depression and aggression also manifest as the disease progresses.
  • the cognitive and behavioral dysfunction is believed to result from altered neuronal function and neuronal loss in the hippocampus and cerebral cortex.
  • the currently available AD treatments are palliative, and while they ameliorate the cognitive and behavioral disorders, they do not prevent disease progression. Therefore there is an unmet medical need for AD treatments that halt disease progression.
  • AD extracellular ⁇ -amyloid
  • a ⁇ extracellular ⁇ -amyloid
  • intracellular neurofibrillary tangles comprised of abnormally phosphorylated protein tau.
  • Individuals with AD exhibit characteristic A ⁇ deposits, in brain regions known to be important for memory and cognition. It is believed that A ⁇ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioral decline.
  • Amyloid plaques consist predominantly of A ⁇ peptides comprised of 40 - 42 amino acid residues, which are derived from processing of amyloid precursor protein (APP). APP is processed by multiple distinct protease activities.
  • APP amyloid precursor protein
  • a ⁇ peptides result from the cleavage of APP by ⁇ -secretase at the position corresponding to the N-terminus of A ⁇ , and at the C- terminus by ⁇ -secretase activity.
  • APP is also cleaved by ⁇ -secretase activity resulting in the secreted, non-amyloidogenic fragment known as soluble APP.
  • BACE-1 An aspartyl protease known as BACE-1 has been identified as the ⁇ -secretase activity responsible for cleavage of APP at the position corresponding to the N- terminus of A ⁇ peptides.
  • a ⁇ has been shown to be toxic to neuronal cells in vitro and when injected into rodent brains.
  • inherited forms of early-onset AD are known in which well-defined mutations of APP or the presenilins are present.
  • Substituted amine BACE-1 inhibitors are disclosed in, WO 04/04396, WO 02/02505, WO 02/02506, WO 02/02512, WP 02/02518 and WO 02/02520.
  • Renin inhibitors comprising a (1 -amino-2 hydroxy-2-heterocyclic)ethyl moiety are disclosed in WO 89/03842.
  • WO 02/088101 discloses BACE inhibitors functionally described as being comprised of four hydrophobic moieties, as well as series of compounds preferably comprising a heterocyclic or heteroaryl moiety.
  • the present invention relates to compounds having the structural formula I
  • R 2 is hydrogen, alkyl or cycloalkyl
  • R 3 is arylene, heteroarylene, heterocyclylene or cycloalkylene
  • R 4 is hydrogen, -C(O)-alkyl, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, heteroaralkyl or heteroaryl;
  • R 5 and R 7 are 1 to 4 moieties, each moiety being independently selected from hydrogen, -OH, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy and alkoxy, with the proviso that when R 5 and R 7 are -OH, aralkoxy, heteroaralkoxy and alkoxy, R 5 and R 7 are not attached to a ring carbon adjacent to a ring nitrogen;
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, alkenyl and alkynyl; or R 9 and R 10 together with the nitrogen to which they are attached, form a 3-7 membered heterocyclyl ring;
  • Y 0 or (H, H); m is O, 1 , 2, or 3; and n is 1 , 2, or 3; wherein each alkyl is optionally substituted with 1 to 3 moieties selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(O)O-alkyl; and wherein each arylene, heteroarylene, heterocyclylalkyl, heterocyclylene, cycloalkylene, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aralkoxy or heteroaralkoxy is optionally substituted with 1 to 4 moieties selected from the group consisting of -CF 3 , alkyl,
  • Compounds represented by formula I are beta-secretase inhibitors useful for the prevention and treatment of Alzheimer's disease.
  • the invention comprises: the method of treating a cardiovascular disease such as hypertension, renal failure, congestive heart failure or another disease modulated by renin inhibition; the method of treating Human Immunodeficiency Virus; the method of treating a cognitive or neurodegenerative disease such as Alzheimer's Disease; the method of inhibiting plasmepsins I and Il for treatment of malaria; the method of inhibiting Cathepsin D for the treatment of Alzheimer's Disease, breast cancer, and ovarian cancer; and the method of inhibiting protozoal enzymes, for example inhibition of Plasmodium falciparnum, for the treatment of fungal infections.
  • Said method of treatment comprise administering at least one compound of formula I to a patient in need of such treatment.
  • the invention comprises the method of treating Alzheimer's Disease comprising administering at least one compound of formula I to a patient in need of such treatment.
  • the invention comprises the method of treating Alzheimer's Disease comprising administering to a patient in need of such treatment a combination of at least one compound of formula I and a cholinesterase inhibitor or a muscarinic mi agonist or m 2 antagonist.
  • the invention relates to a kit comprising in separate containers in a single package pharmaceutical compositions for use in combination, in which one container comprises a compound of formula I in a pharmaceutically acceptable carrier and a second container comprises a cholinesterase inhibitor or a muscarinic Im 1 agonist or m 2 antagonist in a pharmaceutically acceptable carrier, the combined quantities being an effective amount to treat a cognitive disease or neurodegenerative disease such as Alzheimer's Disease.
  • a cognitive disease or neurodegenerative disease such as Alzheimer's Disease.
  • preferred compounds of the invention are those with the following stereochemistry:
  • R 1 can be R 7 wherein n is 2 and R 6 and R 7 are defined herein.
  • R 2 is preferably is alkyl, more preferably methyl .
  • R 3 is arylene or halo-substituted arylene, more preferably phenylene or halo- substituted phenylene, specifically a halo-substituted phenylene, where said halo is preferably fluoride.
  • R 4 is preferably hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, -C(O)Oethyl,
  • R 5 and R 7 independently are alkyl substituted by a cycloalkyl group alkyl or substituted by an aryl or heteroaryl group.
  • R 6 can be aralkyl
  • R 6 is -S(O) 2 -R 8 or more preferably, R 6 is
  • X is a bond connecting R 3 and R 4 , O, alkylene, -alkyl-NHSO 2 - or -alkyl-NHC(O)-;
  • Y is O and n is 2.
  • R 2 is alkyl
  • R 3 is phenylene or halo-substituted phenylene
  • R 4 is hydrogen, -C(O)-alkyl, alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, alkoxyalkyl, heteroaralkyl, substituted heteroaryl, substituted heteroaralkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, substituted heterocyclyl, substituted heterocyclylalkyl or heteroaryl;
  • R 5 and R 7 are hydrogen, alkyl substituted by a cycloalkyl group, alkyl substituted by an aryl or heteroaryl group;
  • R 6 is aralkyl or -S(O) 2 R 8 ;
  • R 2 is preferably methyl
  • R 4 is preferably hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, -C(O)Oethyl,
  • alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like. Further non- limiting examples of cycloalkyl include the following
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • moieties are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heterocyclyl (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 4 to about 7 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), - N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S.S-dioxide.
  • Heterocyclylene means a difunctional group obtained by removal of a hydrogen atom from an heterocyclyl group that is defined above.
  • Non-limiting examples of heterocyclylene include piperidylene, pyrrolidinylene, piperazinylene, morpholinylene, thiomorpholinylene, thiazolidinylene, 1 ,4-dioxanylene, tetrahydrofuranylene and tetrahydrothiophenylene.
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, nor is there an N or S group on a carbon adjacent to another heteroatom.
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, nor is there an N or S group on a carbon adjacent to another heteroatom.
  • heteroarylalkyl or heteroaralkyl and “cycloalkylalkyl” mean a heteroaryl- or cycloalkyl- group in which the heteroaryl, cycloalkyl and alkyl are as previously described. Preferred groups contain a lower alkyl group. The bond to the parent moiety is through the alkyl.
  • Heterocyclylalkyl means a heterocyclyl-alkyl group in which the heterocyclyl and the alkyl are as previously described. The bond to the parent moiety is through the alkyl.
  • Preferred hydroxyalkyls contain lower alkyl.
  • suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkoxyalkyl means an alkoxy-alkyl group in which the alkoxy and alkyl groups are as previously described.
  • suitable alkoxyalkyl groups include ethoxyethyl, methoxymethyl and ethoxymethyl.
  • the bond to the parent moiety is through the alkyl group.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aralkoxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkoxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
  • Alkylheteroaryl means an alkyl-heteroaryl group in which the alkyl and heteroaryl groups are as previously described. The bond to the parent moiety is through the heteroaryl.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-C(O)- group in which the alkyl group is as previously described.
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group in which the aryl group is as previously described.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group in which the aralkyl group is as previously described.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group in which the alkyl group is as previously described. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )- group in which the aryl group is as previously described. The bond to the parent moiety is through the sulfonyl.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl group is as previously described. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the alkyl.
  • Heteroaralkoxy means a heteroaralkyl-O- group in which the heteroaralkyl group is as previously described. The bond to the parent moiety is through the ether oxygen.
  • Heteroarylsulfonyl means a heteroaryl-S(O 2 )- group in which the heteroaryl group is as previously described. The bond to the parent moiety is through the sulfonyl.
  • Heteroarylthio means a heteroaryl-S- group in which the heteroaryl group is as previously described. The bond to the parent moiety is through the sulfur.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • multicyclic divalent groups for example, arylheterocycloalkylene, can be attached to other groups via bonds that are formed on either ring of said group.
  • arylheterocycloalkylene can be attached to other groups via bonds that are formed on either ring of said group.
  • Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group.
  • variables can be the same or different.
  • the wavy line 'vw ⁇ as a b onc j generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry.
  • the possible isomers e.g., containing (R)- and (S)- stereochemistry.
  • polymorphic forms of the compounds of formula I, and of the salts, solvates and prodrugs of the compounds of formula I, are intended to be included in the present invention.
  • isolated or “in isolated form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
  • purified or “in purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C ⁇ jalkyl, (C 2 - Ci 2 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-C ⁇ jalkyl, (C 2 - Ci 2 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to
  • alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C 2 )alkylamino(C 2 -C 3 )alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di (C r C 2 )alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C 2 - C 3 )alkyl, and the like.
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC ⁇ Jalkanoyloxymethyl, 1-((Cr C 6 )alkanoyloxy)ethyl, 1 -methyl-1 -((CrC 6 )alkanoyloxy)ethyl, (C r C 6 )alkoxycarbonyloxymethyl, N-(CrC 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci- C 6 )alkanoyl, ⁇ -amino(Ci-C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (CrCio)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C r C 6 )alkyl, carboxy (Ci-C 6 )alkyl, amino(CrC 4 )alkyl or mono-N — or di-
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • organic bases for example, organic amines
  • benzathines diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting BACE-1 and thus producing the desired therapeutic effect in a suitable patient.
  • a preferred dosage is about 0.001 to 1000 mg/kg of body weight/day of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
  • An especially preferred dosage is about 0.01 to 30 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.
  • This invention is also directed to pharmaceutical compositions for the treatment of neurodegenerative diseases such as Alzheimer's disease which comprise an effective treating amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
  • Still yet another aspect of this invention is a method of treating a cognitive or neurodegenerative disease, such as Alzheimer's disease, comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.
  • a further aspect of this invention is a method for treating a cognitive or neurodegenerative disease such as Alzheimer's disease, comprising administering to a mammal a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.
  • compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
  • This invention is also directed to pharmaceutical compositions for the treatment of neurodegenerative diseases such as Alzheimer's disease which comprise an effective treating amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
  • Still yet other aspects of this invention are combinations of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and other compounds as described below. Accordingly, included within the invention is a method for treating neurodegenerative diseases such as Alzheimer's, comprising administering to a mammal (e.g., a female or male human) a. an amount of a first compound, said first compound being a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound; and b. an amount of a second compound, said second compound being a cholinesterase inhibitor.
  • a mammal e.g., a female or male human
  • anti-inflammatory compounds include but are non limited to non-steroidal anti-inflammatory drugs such as diclofenac (Voltaren, Cataflam), diflunisal (Dolobid), etodolac (Lodine), flurbiprofen (Ansaid), ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen (Orudis, Oruvail), ketorolac
  • non-steroidal anti-inflammatory drugs such as diclofenac (Voltaren, Cataflam), diflunisal (Dolobid), etodolac (Lodine), flurbiprofen (Ansaid), ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen (Orudis, Oruvail), ketorolac
  • HMG-CoA reductase inhibitors for use in combination with compounds of formula I include the "stains," e.g., atorvastatin, lovastatin, simvistatin, pravastatin, fluvastatin and rosuvastatin. Accordingly, included within the invention is a method for treating neurodegenerative diseases such as Alzheimer's, comprising administering to a mammal (e.g., a female or male human) a. an amount of a first compound, said first compound being a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound; and b. an amount of a second compound, said second compound being a N- methyl-D-aspartate receptor antagonist.
  • a suitable N-methyl-D-aspartate receptor antagonist is, for example, memantine.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound is administered orally.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the active components may be co ⁇ administered simultaneously or sequentially, or a single pharmaceutical composition comprising a compound of formula I and one of the other agents in a pharmaceutically acceptable carrier can be administered.
  • the components of the combination can be administered individually or together in any conventional oral or parenteral dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
  • the dosage of the ⁇ -secretase inhibitors other than those of formula I, HMG-CoA reductase inhibitor, gamma-secretase inhibitor, non-steroidal anti-inflammatory agent, N-methyl-D-aspartate receptor antagonist, cholinesterase inhibitor or anti-amyloid antibody can be determined from published material, and may range from 0.001 to 100 mg/kg body weight.
  • the invention also includes multi-agent compositions, kits and methods of treatment, e.g., a compound of formula I can be administed in combination with an HMG-CoA reductase inhibitor and a non-steroidal anti-inflammatory agent
  • a compound of formula I can be administed in combination with an HMG-CoA reductase inhibitor and a non-steroidal anti-inflammatory agent
  • Compounds of Formula I can be produced by processes known to those skilled in the art using either solution phase or solid phase synthesis as shown in the following reaction schemes, in the preparations and examples below, but those skilled in the art will recognize that other procedures can also be suitable.
  • Triphenylphosphine PPh 3
  • Tetrabutylammonium fluoride TBAF Triethylamine: Et 3 N, NEt 3 Or TEA
  • Lithium borohydride LiBH 4
  • BACE-I Cloning, Protein Expression and Purification A predicted soluble form of human BACE1 (sBACEI , corresponding to amino acids 1-454) was generated from the full length BACE1 cDNA (full length human BACE 1 cDNA in pCDNA4/mycHisA construct; University of Toronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, CA).
  • a Hindlll/Pmel fragment from pCDNA4-sBACE1 myc/His was blunt ended using Klenow and subcloned into the Stu I site of pFASTBACI(A) (Invitrogen).
  • IC 50 determinations for inhibitors were determined by measuring the percent change of the relative fluorescence at 665 nm divided by the relative fluorescence at 620 nm, (665/620 ratio), in the presence of varying concentrations of / and a fixed concentration of enzyme and substrate.
  • Nonlinear regression analysis of this data was performed using GraphPad Prism 3.0 software selecting four parameter logistic equation, that allows for a variable slope.
  • Y Bottom + (Top-Bottom)/ (1 Slope));
  • X is the logarithm of concentration of I
  • Y is the percent change in ratio and Y starts at bottom and goes to top with a sigmoid shape.
  • Compounds of the present invention have an IC 5O range from about 100 to about 10,000 nM, preferably about 100 to about 1000 nM, more preferably about 100 to about 500 nM.
  • Compounds of the preferred stereochemistry have IC 5O values in a range of about 2 to about 500 nM, preferably about 2 to about 100 nM.
  • the compound of the following formula has a IC 50 Of 186 nM.

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Abstract

L'invention porte sur de nouveaux composés de la formule (I) ou un sel ou un solvant pharmaceutiquement acceptables de ceux-ci, R1, R2, R3, R4 et X étant tels que définis dans le descriptif. L'invention concerne aussi des compositions pharmaceutiques contenant les composés de la formule (I). Elle se rapporte également à des procédés de traitement de maladies cognitives ou neurodégénérescentes tels que la maladie d'Alzheimer. L'invention concerne aussi des procédés de traitement d'une maladie cognitive ou neurodégénérescente consistant à administrer à un patient ayant besoin de ce traitement une combinaison d'au moins un composé de la formule (I) et au moins un composé choisi dans le groupe des inhibiteurs de ß-secretase autres que ceux de la formule (I), des inhibiteurs de HMG-CoA reductase, des inhibiteurs de gamma-secretase, des agents anti-inflammatoires non stéroïdiques, des antagonistes du récepteur de N-methyl-D-aspartate, des inhibiteurs de cholinesterase et des anticorps anti-amyloïdes.
PCT/US2005/025780 2004-07-22 2005-07-20 Inhibiteurs d'amide beta secretase substitues Ceased WO2006014762A1 (fr)

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DE602005025363T DE602005025363D1 (de) 2004-07-22 2005-07-20 Substituierte amide als inhibitoren der beta-sekretase
MX2007000760A MX2007000760A (es) 2004-07-22 2005-07-20 Amida sustituida inhibidora de b secretasa.
CA002574218A CA2574218A1 (fr) 2004-07-22 2005-07-20 Inhibiteurs d'amide beta secretase substitues
JP2007522711A JP2008507538A (ja) 2004-07-22 2005-07-20 置換アミドβセクレターゼインヒビター
AT05773473T ATE491693T1 (de) 2004-07-22 2005-07-20 Substituierte amide als inhibitoren der beta- sekretase
EP05773473A EP1781625B1 (fr) 2004-07-22 2005-07-20 Inhibiteurs d'amide beta secretase substitues

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US20110003825A1 (en) 2011-01-06
ES2355733T3 (es) 2011-03-30
TW200621249A (en) 2006-07-01
MX2007000760A (es) 2007-04-09
AR049726A1 (es) 2006-08-30
EP1781625A1 (fr) 2007-05-09
ATE491693T1 (de) 2011-01-15
CA2574218A1 (fr) 2006-02-09
EP1781625B1 (fr) 2010-12-15
DE602005025363D1 (de) 2011-01-27
US20060040994A1 (en) 2006-02-23
CN101014577A (zh) 2007-08-08
US7803802B2 (en) 2010-09-28
JP2008507538A (ja) 2008-03-13
US8367712B2 (en) 2013-02-05

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